Clinicians currently do not have methods to predict influenza vaccine responses in older adults that are accessible and relatively inexpensive. The long-term goal of this research is to identify the T-cell responses that are surrogates (biomarkers) of serious complications of influenza and can be used to predict vaccine effectiveness. Such loosely termed biomarkers would provide clinicians with the ability to decide who might benefit from newer or more reactogenic vaccines, such as a higher antigen dose vaccine, or who might require chemoprophylaxis during influenza season due to inadequate response to vaccination. This 5-year proposal is a randomized study of split-virus influenza vaccine (SVV) in a high-dose (HD) vs. standard dose (SD) formulation in each of five influenza seasons to define the key determinants of vaccine-mediated protection against influenza and how these immunologic mediators may be enhanced by vaccination with a newly approved high-dose influenza vaccine in frail older subjects. This study will allow us to address the following aims: AIM I: Determine whether a newly marketed high dose vaccine performs better than standard doses in achieving protective increases in IFN?:IL-10 ratios and GrzB levels. Our hypothesis is that the proportion of subjects above the threshold level for the IFN?:IL-10 ratio (>10) and/or GrzB (>990 U/mg protein) following vaccination will be significantly higher in those receiving the high-dose SVV vs. standard-dose SVV. AIM II: Evaluate the association of degree of frailty to CMV status and GrzB levels in resting T cells (bGrzB). Frailty represents a validated and measurable state of enhanced vulnerability in older individuals. Our hypothesis is that increasing frailty will be positively associated with higher bGrzB levels. AIM III: Establish predictors of vaccine-mediated protection that can be developed for point-of-care testing. Our hypothesis is that increased levels of frailty, CMV seropositive status, and bGrzB activity are associated with lower cytolytic activity, diminished Th1:Th2 responses to influenza challenge, and an enhanced risk of an influenza illness.